Christine Mayr, MD, PhD

Regulation of gene expression by alternative cleavage and polyadenylation (APA)

After sequencing of the human genome and the genomes of much simpler organisms it was surprising to find that the complexity seen in higher organisms seems not to be due to a higher number of genes but rather to a more elaborate regulation of gene expression. Gene expression is regulated at many different levels including histone modifications, differential binding of proteins at promoter or enhancer regions, alternative splicing as well as regulation at the RNA level. RNA binding proteins predominantly bind to the 3' untranslated regions (3'UTRs) and thus influence mRNA stability, translational efficiency, mRNA export and cytoplasmic localization.

Very recently, a new gene regulatory mechanism that influences the expression levels of proteins was identified. This new mechanism leads to shortening or lengthening of 3'UTRs by recognition of APA signals. It seems that proliferating, activated, transformed and less differentiated cells express mRNAs with shorter 3'UTRs whereas terminally differentiated cells mostly have mRNAs with full-length 3'UTRs. mRNAs with shorter 3'UTRs are found in activated T lymphocytes, in brain neurons after membrane depolarization, in embryonic stem cells and in cancer cells. However, embryonic development and differentiation are associated with lengthening of 3'UTRs.

APA in Cancer

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We found that cancer cell lines often express substantial amounts of mRNA isoforms with shorter 3'UTRs when compared to their normal corresponding tissues or to non-transformed cell lines from these tissues. These shorter mRNA isoforms usually result from APA, typically with loss of 80 to 95 percent of 3'UTR sequence, but without affecting the protein-coding region. The APA has functional consequences, with the shorter mRNA isoforms exhibiting increased stability and typically producing ten-fold more protein, in part through the loss of microRNA-mediated repression. Loss of microRNA-mediated repression accounts roughly for half of the regulation that was lost by recognition of more proximal APA signals. Therefore, we suggest that there must be other, so far unknown repressive elements in 3'UTRs that are as important as microRNA binding sites. Moreover, expression of the shorter mRNA isoform of the proto-oncogene IGF2BP1/IMP-1 leads to oncogenic transformation whereas expression of the full-length, annotated mRNA does not. The high incidence of APA in cancer cells, with consequent loss of 3'UTR repressive elements, suggests a pervasive role for APA in oncogene activation without genetic alteration.

Regulation of APA

We are interested in the regulation of mammalian gene expression and we focus on the mechanism and the biological consequences of APA in normal cells, stem cells and cancer cells.

Selected Publications

Mayr C & Bartel DP. Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673-684 (2009).  

Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470-476 (2008). Epub 2008 Nov 2.  

Mayr C, Hemann MT, Bartel DP. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315, 1576-1579 (2007). Epub 2007 Feb 22.